The long term objective of this project is the development of Photodynamic Therapy (PDT) for application in the clinical management of patients with cancer. This goal will be accomplished by gaining a more completed understanding of the basic mechanisms of PDT and conducting careful clinical studies in order to demonstrate safety and efficacy. The specific aims of the basic science studies are to investigate the fundamental mechanism(s) of PDT action on tumor microstructure. To elucidate further the mechanism(s) of PDT action at the cellular level, different photosensitizers will be studied with respect to cellular uptake/retention kinetics, subcellular localization/binding, subcellular phototoxicity, photosensitizer photobleaching and predictive value of fluorescence for phototoxicity, and mechanism(s) of cellular uptake. Those photosensitizers that show significantly more PDT activity than Photofrin "standard" in the human microvascular endothelial cell cult ure, as well as other culture systems studies will be evaluated. The purpose of these studies will be to elucidate the mechanisms of PDT action by examining each of the photosensitizers with respect to light and drug dosimetry parameters for optimal tumor microvasculature destruction, light and electron microscopic study of the time course of tumor microvasculature destruction and determination of photosensitizer localization in microvasculature structures using electron microscope autoradiography.